ABSTRACT: Project 3 ? Abstract In this proposal, we aim to develop optimized envelope DNA and recombinant protein constructs and a novel portable, low-cost multi-antigen surface electroporation system for the DNA to study DNA- EP prime-protein boost vaccine regimens for human immunodeficiency virus (HIV), in relevant animal models. The proposed product development activities will result in generation of pre-clinical immunogenicity and efficacy data from the selected product candidates and dosing regimens, as well as the cGMP manufacture of the combination vaccine product in preparation for a Phase I human clinical trial. Collectively as a team, we have undertaken substantial prior enhanced DNA+EP and/or recombinant protein gp120/140 clinical and pre-clinical vaccine research and development. These efforts support the development of the novel prime-boost regimens contained within this proposal. We have demonstrated proof-of-concept feasibility data in humans with enhanced DNA+EP (IM delivery in HVTN-080) as well as DNA prime-protein boost (Shan Lu). These studies lay the groundwork for a credible and comprehensive product development program outlined in this proposal with the potential to significantly impact HIV vaccine development. The proposed IPCAVD combines four leading academic partners (U. Penn, Emory, Duke, and U. Mass) with Inovio Pharmaceuticals, an innovative product development company, with established expertise in the research and advanced development and testing of HIV vaccines to provide the NIAID- DAIDS with a low risk, ?Research to Clinic? solution with sufficient manufacturing experience and capacity to fulfill projected needs. Additionally, the team has garnered the support of the HIV Vaccines Trials Network (HVTN) to establish a protocol development team and collaborate to conduct the proposed Phase I clinical trial (letter attached) under this program. Upon successful completion of Project 3, the IPCAVD product development team will have tested a novel multi-envelope protein formulation together with a novel multi-envelope DNA combination with a new minimally invasive portable DNA delivery device and manufactured under cGMP the selected envelope DNA and protein constructs to move into Phase I clinical studies.